Medicament delivery device

ABSTRACT

A medicament delivery device for a mixing process to create a therapeutic substance for delivery within a multi-chambered cartridge, the delivery device includes a distal part with a dose setting mechanism having a housing, a dose setting knob, an injection button, a piston rod capable of moving axially along the longitudinal axis of the housing during dose delivery, and a return ring configured to reset the piston rod to a starting position. The delivery device also includes a proximal part including a cartridge holder configured to accept a multi-chambered cartridge, the cartridge holder including a screw driven sleeve configured for attachment to the distal part and rotation of the screw driven sleeve performing a medicament mixing process within the multi-chambered cartridge.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.17/021,787, filed Sep. 15, 2020, which is a continuation application ofinternational patent application PCT/EP2019/059150, filed Apr. 10, 2019,designating the United States and claiming priority from U.S.provisional applications 62/657,283, filed Apr. 13, 2018, and62/688,153, filed Jun. 21, 2018, and the entire content of the aboveapplications is incorporated herein by reference.

BACKGROUND Field of the Invention

The present disclosure relates to medicament delivery devices,particularly to devices for injecting, administering, infusing,dispensing or delivering a substance, and to methods of making and usingsuch devices. More particularly, it relates to delivery devices foradministering a liquid agent, e.g., a medicinal or therapeutic substanceor product, from a multi-chamber cartridge or ampoule. e.g. atwo-chamber cartridge, multi-chamber container or reservoir,multi-chamber ampoule, etc.

Background of the Invention

There are a number of medicament delivery devices on the market that arecapable of automatically, semi-automatically or manually deliveringdoses of medicament. Of the known type of delivery devices, the“pen-type” injector is popular and is available in both reusable anddisposable designs. Such devices are constructed with dose settingmechanisms that include a variety of inter-acting mechanical componentsto achieve desired functions, such as setting a dose, dose cancellation,and ultimately delivering the set dose. Such devices are typicallydesigned for non-medically trained individuals to self-administermedicaments.

In some cases, users of these medicament delivery devices need to injectmedicaments that must be reconstituted with a solvent or diluent beforeinjection. To that end, the injection device must be able to acceptcartridges that have two or more chambers, for example, one chamber tohold a lyophilized drug product and another chamber to hold thereconstitution solvent. The contents of the two chambers must be mixedbefore the injection can occur.

Some of the conventional pharmaceutical products that would undergolyophilization include bulk pharmaceutical/biopharmaceutical ingredient(chemical or biologics found in nature), protein, collagen, peptide,oligonucleotide, chemical API, enzymes, and mAbs. Lyophilization istypically necessary when the bulk drug ingredients are not stable inliquid or frozen form. This can be due to chemical reactions,degradation, aggregation, biological growth, heat sensitivity, etc.Lyophilization enables longer shelf life, often as long as two-fiveyears and makes it much easier to transport the product. In addition,products can be stored at room temperature. One such example is growthhormone, which cannot be stored for any length of time when dissolved ina liquid. However, to provide successful treatment for growth hormoneproblems, it is typically necessary to introduce such agents into apatient's body tissue in liquid form.

The separate chambers in multi-chambered cartridges are usuallyseparated from one another by displaceable or slidable stoppers (i.e.,pistons). The first or front chamber usually comprises an outlet of thecartridge that sealed by a pierceable membrane (e.g., a septum), theinner cartridge wall and the proximal end face of the first stopper. Thesecond or rear chamber usually is located distally from the firstchamber and is formed by the distal end face of the first stopper, theinner cartridge wall and a second stopper. Along the longitudinal axisof the cartridge and hence along the axis along which the stoppers canbe pushed and slid, a bypass is disposed in the cartridge wall, whichcan be used as a fluid bypass for the solvent or dissolving liquid toflow around the first stopper and into the first chamber. To mix thedrug agent with the dissolving liquid, a pressure is applied to thesecond stopper inside the cartridge, where such pressure is transmittedto the first stopper by the non-compressible dissolving liquid. Once acannula is introduced into the cartridge through the pierceablemembrane, the two stoppers can then be pushed or moved along thelongitudinal axis of the cartridge relative to the inner wall of thecartridge.

As soon as the first stopper has moved so that it lies adjacent to theregion of the bypass, the dissolving liquid passes out of the secondchamber through the bypass and flows into the first chamber containingthe drug agent. The second stopper can be pushed relative to the innerwall and toward the first stopper until it lies adjacent and preferablytouching the first stopper. At this point all of the solvent has beentransferred into the first chamber and the second chamber no longerexists. At this point, a cannula, for example a double-ended pen needle,can be attached to the cartridge holder such the cannula pierces themembrane to establish a fluid connection with the first chamber. Now,when the second stopper is pushed again via a piston rod operativelyassociated with a dose setting mechanism, the first stopper is alsomoved. Movement of the two stoppers in the proximal direction eventuallycauses the reconstituted liquid drug in the first chamber to bedispensed through the cannula. When mixing the drug agent with thedissolving liquid, care must be taken to ensure that the agent is notexposed to excessive flows of the dissolving liquid. Foaming should beavoided during mixing before administering an agent in liquid form intoa patient's tissue and it is typically to vent the cannula that is influid communication with the first chamber.

SUMMARY

It has been determined that although conventional devices may enable themixing of a solvent with a drug agent, many delivery device designs donot allow the drug agent to be mixed slowly to avoid foaming or preventdamage to the agent. Additionally, users of these types of devices canfind it difficult to tell when the mixing procedure is complete, and thedrug agent has therefore been fully dissolved in the dissolving liquidin the desired concentration. This can be especially important whenmultiple injections from a single cartridge are needed. Also,conventional device designs involve the use of a threaded connectionbetween cartridge container and pen injector, which is significantlylonger than that of other pen injectors. In such circumstances, it canbe difficult to manufacture such a long thread on the delivery devicepen injector. Furthermore, in some designs the injectors have a pistonrod return features in the form of a rotating ring. This piston rodreturn ring is manipulated by the user to reset or bring the piston rodback to the rearmost proximal position within the dose settingmechanism. When such a long thread is needed, the piston return ring isno longer accessible.

From the above-noted issues with existing devices, there is a need tohave a multi-chamber cartridge medicament delivery device that allows anon-medically trained user to easily operate the device to perform areconstitution process to result in a liquid medicament formulationimmediately prior to the delivery of a set dose of the medicament. Thedisclosure presented below achieves the above-mentioned goals byproviding a robust and relatively easy to use reconstitution deliverydevice.

This disclosure is directed to drug delivery devices that acceptmulti-chambered cartridges. These devices are sometimes referred toreconstitution drug delivery devices. Such devices can be designed toallow a user to set multiple and varying single doses until all themedicament in the cartridge is expelled. Alternatively, the dose settingmechanism can be designed to only deliver one or more fixed (non-usersettable) doses. In some configurations these devices are known aspen-type injectors.

In one possible embodiment of the present disclosure a medicamentdelivery device or more specifically a two-piece pen-type injector isdescribed comprising a distal part and a proximal part for delivery of amedicament mixed within a multi-chambered cartridge, where a distal partcomprises a dose setting mechanism having a housing, a dose settingknob, an injection button, a piston rod capable of moving axially alongthe longitudinal axis of the housing during dose delivery, and a returnring configured to reset the piston rod to a starting position. Aproximal part comprises a cartridge holder configured to accept amulti-chambered cartridge, where the cartridge holder comprises a screwdriven sleeve configured for attachment to the distal part and whererotation of the screw driven sleeve performs a medicament mixing processwithin the multi-chambered cartridge.

As will be explained in more detail below, the screw driven sleeve canbe threaded and configured to cooperate with a threaded portion ofdistal part. The screw driven sleeve can also have a start positionwhere the screw driven sleeve extends distally from a distal portion ofthe cartridge holder and have an end position where the screw drivensleeve is retracted proximally into a distal portion of the cartridgeholder. Additionally, the screw driven sleeve could also have a snap armlocated on an outside surface.

The cartridge holder is configured and designed to accept amulti-chambered cartridge. In some cases, it is desirable to color codethe cartridge holder to highlight or distinguish between differentmedicaments or strengths of a medicament. The cartridge holder can havemultiple cut-outs or windows that allows a user to view the contents ofthe cartridge, including the movement of the slidable stoppers duringthe reconstitution process. When a two-chambered cartridge is positionedin the cartridge holder a first cut-out can be used to view the secondchamber of the cartridge and a second cut-out or window can be used toview the first or most proximal chamber of the cartridge. This secondwindow can also have a narrowed or constricted section that accepts thebypass of the cartridge to hold the cartridge in place in a snap-innotch. The cartridge holder can also be designed and configured topermanently accept a cartridge, i.e., where once the cartridge isinserted into the cartridge holder it cannot be removed unless thecartridge holder is broken or otherwise destroyed. Alternatively, thecartridge holder can be designed and configured to releasably accept acartridge, such that a user can remove an empty cartridge and replace itwith a new, full cartridge. In this design, the cartridge holder neednot require a snap fitting notch to secure the cartridge in place.

The first chamber of the cartridge will typically contain a freeze driedor lyophilized drug agent and the second chamber will contain the liquidsolvent. The cartridge bypass feature is preferably visible through thesecond window. The progress of the lyophilization, i.e., thereconstitution process, can be viewed in both windows. In one embodimentof the present disclosure, a user can view through the first window themovement of the return ring as the cartridge holder is being screwedonto the proximal end of the dose setting mechanism. In all embodiments,the second window will allow viewing of the first and/or second stoppersduring the reconstitution process.

In one embodiment of the device disclosed, the screw driven sleeve canbe designed as a reusable part or as a disposable part. In both casesthe sleeve has a first or starting position where it extends distallyfrom the distal end of the distal portion of the cartridge holder. Whenthe screw driven sleeve is designed as disposable, then the cartridgeholder and the cartridge are also disposable so the assembly isdiscarded as a unit once removed from the dose setting mechanism whichis reused with a new cartridge holder, sleeve and cartridge assembly.Alternatively, the cartridge holder and the screw driven sleeve can bedesigned and configured such that only the empty cartridge is removedand discarded, and a new, full cartridge is inserted into the cartridgeholder and the sleeve is again attached to the dose setting mechanism.In a third possible embodiment, the sleeve is reusable and removablefrom the cartridge holder such that the cartridge and cartridge holderare discarded after use. A new cartridge holder and cartridge assemblywould be attached to the reusable sleeve. In each possible sleevedesign, the distal portion of the cartridge holder has two cut-outs orsnap windows, one at the distal end and one at the proximal end. Thesesnap windows are configured to interact with a flexible or snap armlocated on the outside of the proximal end of the screw driven sleeve.

The snap arm on the screw driven sleeve can have an outward radiallyextending protrusion designed to engage each of the snap windows. Whenthe screw driven sleeve is in the first position, the snap arm isreleasably engaged with the distal snap window and when thereconstitution process is complete, the screw driven sleeve is fullypositioned inside the distal portion of the cartridge holder and thesnap arm is engaged with the proximal snap window. In the design wherethe assembly of the cartridge holder, cartridge and sleeve are alldisposable, the engagement of the protrusion with the proximal snapwindow is non-releasable, i.e., permanent, such that the sleeve cannotbe rotated relative to the distal portion of the cartridge holder. Inthe case where the sleeve is reusable, the protrusion and proximal snapwindow form a releasable engagement such that an applied rotation torquewill disengage the protrusion from the proximal snap window and allowthe sleeve to be rotated relative to the cartridge holder. The snap armis designed such that the protrusion will fit into the proximal snapwindow when the screw driven sleeve is moved axially inside thecartridge holder and becomes aligned with a snap window. As the screwdriven sleeve moves relative to the inside surface of cartridge holder,the protrusion and snap arm are biased radially inward. When theprotrusion becomes aligned with a snap window, the snap arm is free toflex radially outward so that the protrusion engages or snaps into thewindow.

The outside surface of the screw driven sleeve can have a helical orouter screw thread that can engage and cooperate with a like threadlocated on the inside of the distal portion of the cartridge holder. Theouter thread can be a male thread or a female thread. In the lattercase, the inside of the distal portion of the cartridge holder couldhave one more nibs that engage with the female thread as opposed tohaving a full set of male threads. On the inside distal end of the screwdriven sleeve is a fastener that cooperates with a like fastener on thedose setting mechanism. The cooperation of these fasteners allows thedistal and proximal parts of the medicament delivery device to bereleasably or permanently connected to each other. When a permanentconnection is desired the fasteners could cooperate to form anirreversible snap fit. Alternatively, the permanent joint or connectionformed by the fasteners could be welded or glued to result in apermanent connection between the dose setting mechanism and the screwdriven sleeve such the delivery device would have to be physicallybroken in order to separate these parts.

In another embodiment, the presently disclosed device is configured suchthat the reconstitution process requires that the piston rod return ringbe rotated so as to move the piston rod axially in the proximaldirection as the cartridge holder/cartridge assembly is connected to thedose setting mechanism. In the case where the injection device isreusable, then before the assembly is attached to the dose settingmechanism, the piston rod has to be retracted to the rearmost or startposition by rotating a piston rod return ring counter clockwise relativeto the dose setting mechanism. In the case of a completely disposabledevice, there would be no need to retract the piston rod and thereforethe device would not need to have piston rod return ring. Because thereturn ring is rotatably fixed with the piston rod, rotation of thereturn ring causes the piston rod to rotate. A threaded connectionbetween the piston rod and an internal stationary nut in the dosesetting mechanism causes the piston rod to axially move distal orretract back into the dose setting mechanism. Likewise, when the pistonrod return ring is turned in a clockwise direction relative to the dosesetting mechanism, the piston rod will move axially in the proximaldirection, i.e., extend out and away from the dose setting mechanism.The present device is configured such that as the cartridge holder isscrewed onto or into the dose setting mechanism by turning it clockwiserelative to the dose setting mechanism in a customary and normalprocedure, such rotation also rotates the return ring in the sameclockwise direction. This results in the piston rod and the distal moststopper in the cartridge moving axially relative to each other as thecartridge holder is attached to the dose setting mechanism. Thesimultaneous rotation of the return ring and cartridge holder relativeto the dose setting mechanism allows the length of the thread on the peninjector to be much less than a conventional reconstitution injectiondevice because of the simultaneous axial movement of the piston rod andcartridge holder in opposite directions as a result of the cartridgeholder rotating the return ring.

Preferably an interior portion of the distal end of the cartridge holderis threaded with a screw thread that matches and cooperates with anexternal threaded proximal end of the dose setting mechanism. Theinterior distal portion of the cartridge holder can also contain one ormore guide elements that can rotational engage the return ring when theproximal part (i.e., the cartridge holder) and the distal part (i.e.,the dose setting mechanism) are axially aligned with each otherimmediately before the two parts are screwed together. The engagement ofthe guide element with the return ring allows the return ring to berotated as the cartridge holder is screwed into or onto the dose settingmechanism. Preferably a splined engagement is used between the guideelement and the outside surface of the return ring. Such an engagementmust allow for relative axial movement between the guide element and thereturn ring as the distal and proximal parts are screwed together. In apreferred configuration two or more guide elements are used, preferablyequally spaced around the inside surface of the cartridge holder. Thecartridge holder can be designed as a reusable part or as a disposablepart. When the cartridge holder is designed as disposable, then thecartridge is also disposable, so the assembly is discarded as a unitonce removed from the dose setting mechanism which is reused with a newcartridge holder and cartridge assembly. Alternatively, the cartridgeholder can be designed and configured such that only the empty cartridgeis removed and discarded, and a new, full cartridge is inserted into thecartridge holder and the assembly is again attached to the dose settingmechanism.

An outside surface of the proximal end of the dose setting mechanism canhave a helical or outer screw thread that can engage and cooperate witha like threaded surface located on the inside of the distal portion ofthe cartridge holder. Of course, the device could also be manufacturedsuch that the threaded surfaces are reversed, i.e., there is a thread onthe outside surface of the cartridge holder and a cooperating thread onthe inside of the dose setting mechanism. The outer thread on the dosesetting mechanism can be a male thread or a female thread. In the lattercase, the inside of the distal portion of the cartridge holder couldhave one more nibs that engage with the female thread as opposed tohaving a full set of male threads. When a permanent connection isdesired between the cartridge holder and the dose setting mechanism,there could be included a non-releasable snap lock fitting that engageswhen the distal and proximal parts are screwed securely together. Suchan irreversible lock will prevent a user from disassembling these partsin the absence of physically braking one or more components of thedelivery device in order to separate these parts.

For each embodiment disclosed, the delivery device can be designed andconfigured as a reusable or a semi-reusable device, where (1) thecartridge, cartridge holder and sleeve assembly can be replaced once themedicament has been expelled and the dose setting mechanism is reused,(2) the sleeve and the dose setting mechanism are reused and thecartridge holder and cartridge are disposed of, or (3) the cartridgeholder, sleeve and dose setting mechanism are reusable and only theempty cartridge is removed and discarded, and (4) the entirereconstitution device is disposed of after the medicament in thecartridge is expelled. In the designs where the dose setting mechanismis reusable, then the fastener on the screw driven sleeve and thecooperating fastener on the dose setting mechanism should also bereusable, i.e., releasably cooperating, for example, a screw thread, aLuer-Lok fitting, a bayonet fitting, detent or a combination of thesereliable type connectors. Such a releasable connection allows a user toseparate the sleeve from the dose setting mechanism without damaging thedose setting mechanism. In order to reuse the dose setting mechanism thepiston rod must be retracted back into the dose setting mechanism. Thisis referred to as a resetting operation.

In another embodiment where the delivery device is designed andconfigured as a disposable device, a reusable or a semi-reusable device,(1) the cartridge and cartridge holder can be replaced once themedicament has been expelled and the dose setting mechanism is reused,(2) the cartridge holder and dose setting mechanism are reusable andonly the empty cartridge is removed and discarded, and (3) the entirereconstitution device is disposed of after the medicament in thecartridge is expelled. In a completely disposable of this device design,there is no need to retract the piston rod after the medicament in thecartridge is expelled because the entire device is thrown away. However,initially when the cartridge holder/cartridge assembly is attached tothe dose setting mechanism, the rotation of the cartridge holder as itis screwed into/onto the dose setting mechanism will rotate a piston rodguide as opposed to a piston rod return ring. The function of the pistonrod guide in a completely disposable device is similar to the piston rodreturn ring in that that it is axially fixed to the housing and rotationin a clockwise direction causes the piston rod to move proximally toperform the reconstitution process. Once the cartridge holder is fullyattached to the dose setting mechanism the connection becomes fixed,permanent and irreversible, thus preventing a user from disassemblingthe cartridge holder from the dose setting mechanism without physicallybreaking or destroying the device.

In the designs where the dose setting mechanism is reusable, then thefastener or threaded connection on the cartridge holder and thecooperating fastener or thread on the dose setting mechanism should alsobe reusable. Such a releasable connection allows a user to separate thecartridge holder from the dose setting mechanism without damaging thedose setting mechanism. In order to reuse the dose setting mechanism thepiston rod must be retracted back into the dose setting mechanism usingthe return ring described above by turning the return ring in thecounter-clockwise direction. Again, as mentioned, this retraction of thepiston rod to a start position is referred to as a resetting operation.

In one possible embodiment of the reconstitution delivery device, thefollowing procedure can be followed. With the cartridge positioned in acartridge holder, the inner thread of the screw driven sleeve isthreadedly engaged with the thread located at the proximal end of thedose setting mechanism. The screw driven sleeve is turned until theterminal distal end face of the sleeve abuts and contacts a terminalproximal end face on the housing of the dose setting mechanism such thatthe sleeve can no longer be rotated relative to the housing. Asmentioned, the cartridge is held in place in the proximal portion of thecartridge holder through the snap-in notch that accepts the radiallyprotruding bypass section of the cartridge. Preferably, thereconstitution device is provided to the end user with the cartridgesnapped into the cartridge container and the screw driven sleeve snappedinto the distal portion of the cartridge holder through engagement ofthe snap arm with the first snap window. The solvent can be inspectedthrough the first observation window and the lyophilizate can beinspected through the second observation window.

When the two terminal end faces are in abutment, the proximal end of thepiston rod will also be abutment with the distal end face of the secondstopper in the cartridge. Rotation of the cartridge holder relative tothe screw driven sleeve will cause the snap arm to disengage from thefirst or distal snap window and allow the sleeve to be screwed into thedistal portion of the cartridge holder. Because the protrusion of snaparm is engaged into the first snap window of the cartridge holder, acertain torque has to be applied, before the cartridge holder can rotaterelative to the sleeve. Once this initial torque has been applied, thetorque to turn the cartridge container relative to the sleeve is low dueto the large pitch of the threaded connection between the sleeve and theinside of the cartridge holder. Only when the sleeve is fully screwed tothe housing of the dose setting mechanism can the cartridge holder startturning relative to the sleeve, which takes the cartridge holder towardsthe dose setting mechanism and as such starts the reconstitutionprocess. Thus, a first purpose of the snap arm on the sleeve ensuresthat the cartridge holder only starts to turn relative to the sleevewhen the sleeve is fully attached to the dose setting mechanism. Thesecond purpose of the snap arm becomes evident in the designs where thesleeve is disposable. Here the permanent engagement of the snap arm withthe proximal snap window ensures that the user cannot disassemble theassembly when the reconstitution process is completed. Thus, rotation ofthe cartridge holder in a counter-clockwise direction will unscrew thesleeve from the proximal end of the dose setting housing and then theassembly of the cartridge holder, cartridge and sleeve can be disposedof as a single unit.

Once the distal end of the sleeve is fully fastened to the housing ofthe dose setting mechanism, a cannula can be used to pierce the membraneto form a fluid communication with the first chamber in the cartridge.This fluid communication is necessary to allow the reconstitutionprocess to continue by acting a pressure relief or vent of the firstchamber. With the cannula in place, the cartridge holder can then berotated relative to both the sleeve and the attached dose settingmechanism, the cartridge holder and cartridge are moved together towardsthe stationary proximal end of the piston rod. This causes the pistonrod to exert an axial force in the proximal direction on the secondstopper causing it to move proximally relative to the inside wall of thecartridge. Because the liquid solvent in the second chamber isincompressible the force on the second stopper is directly transferredto the first stopper such that both stoppers, and the solvent locatedbetween them, each move axially forward (proximally) towards the bypasssection of the cartridge. Any excess pressure in the first chamber as aresult of this transferred force from the piston rod is relieved throughthe cannula. Once the first stopper has moved into alignment with thebypass, the solvent can then flow from the second chamber around thefirst stopper and empty into the first chamber where it contacts thelyophilized drug agent and reconstitution begins. The pressure of thesolvent from the moving second stopper is reduced as the liquid solventflows through the bypass.

As the cartridge holder continues to rotate and move relative to thescrew driven sleeve, the cartridge continues to move relative to thestationary piston rod, thus pushing the second stopper axially in aproximal direction inside the cartridge until all the solvent is forcedout of the second chamber and into the first chamber. The two stopperseventually abut and contact each other and continue to move togetherproximally relative to the inside wall of the cartridge. When thestoppers abut, the second chamber ceases to exist. When the cartridgeholder is fully screwed onto the screw driven sleeve the snap armbecomes aligned with the proximal snap window and the protrusion engagesinto the snap window securing the screw driven sleeve axially in place.As mentioned, this engagement of the snap arm with the proximal snapwindow can be permanent, thus irreversibly locking the sleeve to thecartridge holder, or in the case of reusable sleeve, this engagement canbe releasable. In either event, once the reconstitution process iscomplete, the proximal face of the second stopper is now abutting thedistal face of the first stopper, essentially acting and functioning asa single stopper to allow for dispensing a set dose as explained below.

The user can now view, inspect and evaluate the reconstituted productthrough the second observation window. The user then attaches a needleassembly to the proximal end of the proximal portion of the cartridgeholder such that a cannula or injection needle pierces the scalingmembrane in the cartridge and establishes a fluid communication with thefirst chamber. At this point the reconstitution delivery device can beprimed and then one or move doses can be set and delivered to the user.

In another possible embodiment of the reconstitution delivery device,the following procedure can be followed. With the cartridge positionedwithin the cartridge holder a cannula can be used to pierce the membraneto form a fluid communication with the first chamber in the cartridge.This fluid communication is necessary for the reconstitution process tocontinue by acting a pressure relief or vent of the first chamber of thecartridge. This assembly of the cartridge holder, cartridge and cannula,is then axially aligned with the dose setting mechanism having thepiston rod retracted to the start position. The assembly is move axiallytowards the dose setting mechanism until the guide element on thecartridge holder engages with the return ring to form a rotationallyfixed, but slidable, connection. The assembly and the dose settingmechanism are moved together until the threads on the two parts engageand the parts can now be screwed together. At this point, preferably theterminal proximal end of the piston rod is abutting the distal facingsurface of the second stopper. Further rotation will begin thereconstitution process because rotation of the cartridge holder causesrotation of the return ring which in turn causes the piston rod to moveaxially in the proximal direction and to engage the distal most pistonas further explained below.

The axial proximal movement of the piston rod causes the piston rod toexert an axial force in the proximal direction on the second (distalmost) stopper causing it to move proximally relative to the inside wallof the cartridge. Because the liquid solvent in the second chamber isincompressible the force on the second stopper is directly transferredto the first stopper such that both stoppers, and the solvent locatedbetween them, each move axially forward (proximally) towards the bypasssection of the cartridge. Any excess pressure in the first chamber as aresult of this transferred force from the piston rod is relieved throughthe cannula. Once the first (proximal most) stopper has moved intoalignment with the bypass, the solvent can then flow from the secondchamber around the first stopper and empty into the first chamber whereit contacts the lyophilized drug agent and begins solubilizing the drugagent. The pressure of the solvent from the moving second stopper isreduced as the liquid solvent flows through the bypass.

As the cartridge holder is further rotated and moving axially relativeto the dose setting mechanism, the cartridge and piston rod continue tomove relative to each other and the piston rod continues pushing thesecond stopper axially in a proximal direction inside the cartridgeuntil all the solvent is forced out of the second chamber and into thefirst chamber. The two stoppers eventually abut and contact each otherand continue to move together proximally relative to the inside wall ofthe cartridge. When the stoppers abut, the second chamber ceases toexist. This should occur when the cartridge holder is fully screwed intoor onto the dose setting member and the two parts abut each other. Oncethe reconstitution process is complete, the proximal face of the secondstopper is now abutting the distal face of the first stopper,essentially acting and functioning as a single stopper to allow fordispensing a set dose as explained below.

As previously indicated, the user can now view, inspect and evaluate thereconstituted product through the second observation window. At thispoint the reconstitution delivery device can now be primed and one ormore doses can be set and delivered to the user.

A reversible snap fit can be included at the terminal end of thethreaded connection between the cartridge holder and the dose settingmechanism so that the two parts will not easily unscrew from each otherduring use. The reversible snap can be designed such that a user willhave to supply a certain amount of rotational torque in order todisconnect the snap fit and allow the cartridge holder/cartridgeassembly to rotate in a counter-clockwise direction until it can beremoved from the dose setting mechanism.

As mentioned, the cartridge is held in place in the proximal portion ofthe cartridge holder through the snap-in notch that accepts the radiallyprotruding bypass section of the cartridge. Preferably, thereconstitution device is provided to the end user with the cartridgesnapped into the cartridge holder such that the solvent can be inspectedthrough the first observation window and the lyophilizate can beinspected through the second observation window.

These and other aspects of, and advantages with, the present disclosureswill become apparent from the following detailed description of thepresent disclosure and from the accompanying drawings.

BRIEF DESCRIPTION OF DRAWINGS

In the following detailed description of the present disclosure,reference will be made to the accompanying drawings, of which

FIG. 1 is an illustration of one possible dose setting mechanism thatforms the distal section of one embodiment of the completereconstitution medicament delivery device of the present disclosure;

FIGS. 2A and 2B illustrate two views of a possible proximal section ofthe device of FIG. 1;

FIGS. 3A-3D illustrate several views of the complete delivery devicewhere the proximal and distal sections of FIGS. 1 and 2A and 2B areconnected and the device is in a first or starting configuration;

FIGS. 4A and 4B illustrate the screw driven sleeve of the device ofFIGS. 3A-3D and a cross-sectional view of same;

FIGS. 5A-5E show several views of a dual chambered cartridge than can beused in the device of FIGS. 3A-3D;

FIGS. 6A-6D illustrate several views of the complete delivery deviceafter reconstitution in second or ready-to-inject configuration;

FIGS. 7A-7E illustrate another possible embodiment of the device of thepresent disclosure where the cartridge holder and screw driven sleeveassembly is reusable;

FIGS. 8A-8C illustrate several views of a reusable screw driven sleeve;

FIGS. 9A and 9B illustrate several views of a reusable cartridge holder,and

FIGS. 10A-10D illustrate the changing configurations of a possible dosesetting mechanism as a user sets and then delivers a dose of medicament.

FIG. 11 is an illustration of one possible dose setting mechanism thatforms the distal section of one embodiment of the completereconstitution medicament delivery device of the present disclosure;

FIGS. 12A-12D illustrate four views of the return ring of the device ofFIG. 11;

FIGS. 13A-13C illustrate three views of one possible design of thecartridge holder present disclosure configured for connection to thedose setting mechanism of FIG. 11;

FIGS. 14A-14F illustrate several views of the medicament delivery deviceof the present invention in three different stages of assembly;

FIGS. 15A and 15B illustrate two views of the complete delivery deviceafter reconstitution in the second or ready-to-inject configuration;

FIGS. 16A-16E show several views of a dual chambered cartridge than canbe used in the cartridge holder of FIG. 13;

FIGS. 17A-17C illustrate a sequence of a possible dose setting mechanismfor the dose setting mechanism of FIG. 11; and

FIGS. 18A-18F illustrate several view of an alternative fully disposabledesign of the cartridge holder of the present disclosure configured forconnection to a disposable dose setting mechanism.

DETAILED DESCRIPTION

In the present application, the term “distal part/end” refers to thepart/end of the device, or the parts/ends of the components or membersthereof, which in accordance with the use of the device, is located thefurthest away from a delivery/injection site of a patient.Correspondingly, the term “proximal part/end” refers to the part/end ofthe device, or the parts/ends of the members thereof, which inaccordance with the use of the device is located closest to thedelivery/injection site of the patient.

FIGS. 1 and 2A and 2B illustrate the two sections of a semi-disposabledevice 1 that when connected together (see FIGS. 3A-3D) form onepossible complete reconstitution medicament delivery device of thepresent disclosure. By “semi-disposable” it is meant that the dosesetting mechanism is reusable and the cartridge holder and/or the screwdriven sleeve is designed and configured to be disposed of along withthe empty cartridge after the medicament has been expelled. A“completely disposable” device is one where the sleeve is permanentlyconnected to the dose setting housing and after the reconstitutionprocess the sleeve is also permanently attached to the cartridge holdersuch that after the expulsion of the medicament, the entire device isdisposed of.

The proximal section 2 of device 1 includes the dose setting mechanism.The distal section 3 includes cartridge holder 50 and screw drivensleeve 16, where the cartridge holder includes a distal portion 17 and aproximal portion 40. The dose setting mechanism 2 includes housing 4,piston rod 11, piston return ring 12 (i.e., part of a piston rod resetfeature), dose knob 5, button 6, and window 7 to view dose settings 8.At the proximal end of housing 4 is a first thread 9 and may include aradial stop 10 that works to clearly define the radial position of thecartridge holder in the ready-to-use state. The radial stop 10 isdesigned to interact and abut a cooperating stop 51 on the terminaldistal end of distal portion 17 of the cartridge holder when the screwdriven sleeve 16 is fully retracted into the cartridge holder and whensnap arm 32 engages the proximal snap window 30.

The cartridge holder 50 accepts and securely holds cartridge 35,preferably through a snap fit connection between the bypass 21 and notch20 located on the second observation window 22 (see FIGS. 2A and 2B).The bypass 21 is part of cartridge 35 and allows the solvent 37 (seeFIGS. 5A-5E) to flow from the second or distal chamber 18 into the firstor proximal chamber 19 during the reconstitution process where thesolvent solubilizes the lyophilized drug agent 38. The lyophilized drugis typically prepared in a lyophilization process that generallyinvolves three stages; freezing, primary drying, and secondary drying.Freezing takes place in a freeze dryer, however, a conventional freezercan also be instead. Freezing temperatures are around −40° C. and thereis no thawing before the drying stages. The frozen product goes fromfrozen state to dry powder through the process of sublimation at reducedpressure to cause the frozen water to sublime directly from the solidphase to the gas phase leaving a dry powder. The solvent used torehydrate the lyophilized drug agent is typically water or could be anyliquid that solubilizes the lyophilized drug and is biocompatible as aninjectable material.

The cartridge holder 50 has two observation windows 22, 23. Window 23can be a cut-out in the distal portion 17 of the cartridge holder. Thiswindow 23 allows the user to observe the solvent 37 that is initiallycontained in chamber 18 when the device is in the startingconfiguration. As the reconstitution process begins window 23 will showthe axial movement of sleeve 16 as it is screwed or retracted intocartridge holder 50. Window 22 is located in the proximal portion 40 ofthe cartridge holder and can also be a cut-out. Window 22 may also havenotch 20 that is designed to engage and secure bypass 21 of thecartridge 35 through, for example, a snap fit connection. This windowalso allows the user to view the lyophilized drug agent before, duringand after the reconstitution process.

The exemplary multi-compartment cartridge 35 (see FIGS. 5A-5E) is shownas a dual chamber cartridge comprised of a first or proximal chamber 19and a second or distal chamber 18. These chambers are separated by asliding piston or stopper, namely first stopper 26, the proximal end ofchamber 19 is sealed by pierceable membrane or septum 37 that is securedin place by a crimped metal cap 36. The proximal end of cartridge 35 issealed by a second sliding stopper 25. Solvent 37 is contained betweenstoppers 25,26. Lyophilizate 38 containing the drug agent is in firstchamber 19. FIGS. 5A-5E show the movement and changing chamberconfiguration during the reconstitution process as the delivery devicetransforms from the initial or starting configuration (see FIGS. 3A-3D)and progresses to the delivery ready configuration shown in FIGS. 6A-6D.The flow of solvent around the first stopper is also illustrated byarrows 41.

The screw driven sleeve 16 (see FIGS. 4A and 4B) is tube-like cylinderhaving an internal thread 14 located on the inner proximal surface. Theoutside surface of sleeve 16 has a thread 15 configured to engage acooperating thread 55 located inside the distal portion 17 of thecartridge holder (see FIGS. 2A and 2B). In some designs, thread 15 canbe a female thread, e.g., a helical groove, that will engage a niblocated on the inside surface of distal portion 17. The proximal end ofsleeve 16 has at least one flexible or snap arm 32 that has a protrusion33 that projects radially outward relative to the longitudinal axis 45,which is also the axis of device 1 and cartridge 35. This protrusion isdesigned to fit into both the proximal and distal snap windows 30,31that are configured as cut-outs in proximal portion 17 of cartridgeholder 50. The flexible snap arm 32 is designed to flex radially inwardas the cartridge holder is rotated relative to the screw driven sleeve16 causing the sleeve to be retracted into the cartridge holder duringthe reconstitution procedure. Once the cartridge holder has been fullyscrewed to the sleeve, the protrusion 33 becomes aligned with snapwindow 31 and the snap arm flexes radially outward such that theprotrusion fits into and engages window 31. In the design where thecartridge holder and sleeve are disposable, this engagement is permanentsuch that a user will not be able to rotate the cartridge holderrelative to the sleeve. This permanent locking engagement can beachieved by using an asymmetrically shaped protrusion, sometimesreferred to as an irreversible snap lock.

FIGS. 5A-5E shown the position of stoppers 25, 26 relative to bypass 21after the reconstitution process is complete. As illustrated, chamber 18is completely subsumed as stopper 25 has moved proximally and inabutment with stopper 26. At this stage the device 1 is now ready to beprimed and/or to perform an injection once a needle is attached toconnection 24.

The present disclosure is applicable with a number of injection devicedesigns. FIGS. 1 to 6D illustrate just one possible type of pen-shapedinjection design as being a semi-disposable device, where the only thedose setting mechanism is designed and configured for reuse. In such adevice, after the reconstitution process is complete and after themedicament has been expelled from the cartridge, the user detaches thecartridge holder/screw driven sleeve assembly containing the emptycartridge from the reusable dose setting mechanism and discards theassembly. A new assembly, containing a fresh cartridge, can then beconnected to the dose setting mechanism and the reconstitutionprocess/medicament delivery sequence can be repeated. The used cartridgeholder/screw driven sleeve assembly is characterized in that the screwdriven sleeve is fully contained within (i.e., screwed into) thecartridge holder and no part of it is accessible by the user. Further,because the snap arm is in a permanent connection with the proximal snapwindow, even if the user tried to turn the screw driven sleeve thepermanent connection would prohibit any relative rotational movementbetween the cartridge holder and screw driven sleeve.

For a device design where the either the cartridge holder or screwdriven sleeve or both are to be reused, it is necessary to unscrew thescrew driven sleeve from the inside of the cartridge holder. To thatend, it is helpful to provide a user assist component. FIGS. 7A to 9Billustrate a device design where the screw driven sleeve and thecartridge holder is to be reused. In order to reuse the screw drivensleeve 60, it is necessary to have a releasable or non-permanentengagement between the snap arm 63 and the proximal snap window suchthat the cartridge holder 61 can be rotated relative to the screw drivensleeve 60 along thread 66. This will cause the screw driven sleeve 60 toextend outward of the inside of the cartridge holder and return to thestarting position. This releasable engagement can be achieved by using asymmetrical protrusion 64 on snap arm 63 (see FIGS. 8A-8C). As explainedabove, once the medicament delivery is completed, the user will counterrotate the cartridge holder, which will also counter rotate the screwdriven sleeve because of the snap fit of the proximal snap window withthe protrusion on the snap arm. Once the assembly is disconnected fromthe reusable dose setting mechanism, the user must be able to counterrotate the screw driven sleeve to reset the sleeve to the startingposition where the snap arm is releasably engaged with the distal snapwindow. One possible design to assist the user in this resetting of thescrew driven sleeve is to include a knurled ring 62 on the distal end ofthe screw driven sleeve. This gripping surface will provide leverage, sothe user can exert the needed torque to overcome the snap fit betweenprotrusion 64 and the proximal snap window. Ring 62 could also be usedto provide a user leverage to disconnect thread 65 from the dose settingmechanism. Cartridge holder 61 can also have a second or proximal window69 with a reduced section 68 that allows an empty cartridge to beremoved and new, full cartridge 35 to be slid into the cartridge holder61 (see FIGS. 9A and 9B).

Device 1 has a dose dial sleeve that translates in a longitudinaldirection during dose setting, dose correction and dose delivery. A doseis set through rotation of dose knob 5, which causes the dose dialsleeve to move linearly in the distal direction. A dose is delivered bypushing button 6 on the end of the dose knob 5 in the opposite orproximal direction. This in turn causes the dose dial sleeve to movelinearly back (proximally) into the dose setting mechanism 2. Oneexemplary sequence of a possible dose setting mechanism is illustratedin FIGS. 10A-10D, where the dose setting mechanism is shown in thezero-set dose position (“0” on scale 8), when the dose is set, thatstart of the injection when button 6 is pressed, and the end ofinjection where the piston rod has moved proximally an axial distanceproportional to the set dose of medicament. The dose setting mechanismshown in FIGS. 10A-10D is designed and configured to only allow settingof a fixed, single predetermined dose that is signified by “GO” on scale8.

The pen-type injector design shown in the figures will now be describedwith more detail as to the component parts and their operation. Thecomplete injection device 1 is illustrated in the zero-dose state asindicated by scale 8 showing a zero through the window 7 of housing 4(see FIGS. 7A-7E). FIGS. 3A-3D show the device 1 with a protective capremoved to expose the cartridge holder 50 having a proximal needleconnector 24 at the proximal end. A double-ended pen needle is typicallyattached to the needle connector 24 through a snap fit, thread,Luer-Lok, or other secure attachment with that the double ended needlecannula can achieve fluid communication with reconstituted medicament 39within chamber 19 of cartridge 35 positioned within cartridge holder 50.The cartridge 35 is sealed at the proximal end by septum 37 (see FIGS.5A-5E).

As mentioned, the dose setting mechanism can be designed and configuredas a fixed dose device. Alternatively, the dose setting mechanism couldallow for setting of one or more user selected doses through therotation of the dose knob 5 relative to housing 4. Part of the dosesetting mechanism of most pen-type injectors is a piston rod 11 asillustrated in FIGS. 1, 5A-5E and 10A-10D. Such piston rods usually havea non-circular cross-section and have two flat surfaces that aredesigned to prevent the piston rod from rotating but allowing it to movelinearly in the proximal direction. As the piston rod moves proximallyit pushes stoppers 25,26 proximally to expel medicament 39. The pistonrod 11 is held in a non-rotational state relative to housing 4 duringboth dose setting and dose delivery because it is arranged within anon-circular pass through hole in the center of a piston rod guide. Thepiston rod guide is both rotationally and axially fixed to housing 4.This fixation can be achieved when the piston rod guide is a separatecomponent from the housing 4 or the piston rod guide could be madeintegral with the housing.

If the device is not pre-primed during the device assembly or does nothave an automatic or forced priming feature, then the user will need tomanually prime the device as follows. The dose knob 5 is rotated suchthat an amount of medicament 39 will be expelled from cartridge 35. Theinjection device 1 of this disclosure can also have a so-called forcedor automatic priming feature where prior to using the dose settingmechanism, i.e., before a user could dial a dose, a sliding lock orother mechanism would necessarily need to be activated such that anamount of medicament is expelled.

In some instances, the user may need to cancel the priming procedure ora previously set dose. This achieved through a dose canceling procedure.Dose cancellation is accomplished by turning the dose knob in theopposite direction used to set a dose. During dose cancellation, certaincomponents in the dose setting mechanism rotate and translate axially inthe opposite or proximal direction compared to the dose settingprocedure.

During dose setting, the dose knob 5 translates out and away from thedistal end of housing 4. As the dose dial sleeve rotates and translatesdistally, the progress of the dose setting (or dose cancellation) isobserved in window 7 as printed indicia on the dose dial sleeve movespast the window. When a desired dose setting is reached the indicia 8for that dose will appear in the window. At this point the injectiondevice 1 is ready for a priming procedure or, if already primed, thedelivery of the medicament to an injection site. In either the case, theuser will push button 6 on the dose knob in the proximal direction untilthe zero-dose hard stop is reached and a zero-dose indicia is observedin the window. During a priming step the user will observe whethermedicament is expelled out of the cannula of a pen needle. If nomedicament is expelled this means the piston rod is not in abutment withthe distal face of sliding piston or stopper 25. The priming step isthen repeated until medicament is observed exiting the cannula.

The dose setting mechanism of the present disclosure can also have amaximum dose hard stop feature that prevents a user from setting a dosegreater than the highest predetermined dose setting.

Once a dose has been dialed on the dose setting mechanism, the user canthen exert an axial force in the proximal direction on button 6 toinitiate the dose delivery procedure. The axial force exerted by theuser overcomes a distally directed force exerted by a biasing membercausing the piston rod 11 to move axially in the proximal direction.Axial movement of the piston rod causes the sliding stoppers to alsomove axially relative to the inside walls of chamber 19 of thestationary cartridge 35 forcing an amount of medicament 39 out of theneedle cannula 6 that is equivalent to the dose that was set by the userduring the dose setting procedure.

If the device is configured as a disposable injection device, then thecartridge 35 is not replaceable because the connection between thecartridge holder 50 and the housing 4 of the dose setting mechanism 2 ispermanent. Only through breaking or deformation of this connection canthe cartridge be removed from the injection device. Such a disposabledevice is designed to be thrown out once the medicament has beenexpelled from the cartridge.

In an alternate embodiment, FIG. 11 and FIGS. 13A-13C illustrate the twosections of a semi-disposable device 1 that when connected together (seeFIGS. 15A and 15B) form another possible complete reconstitutionmedicament delivery device of the present disclosure. As describedabove, this embodiment can be designed as a “semi-disposable” or“completely disposable” device.

The distal part of device 1 includes the dose setting mechanism 2. Theproximal part 3 includes cartridge holder 50, where the cartridge holderincludes a distal portion 50 b and a proximal portion 50 a. The dosesetting mechanism 2 includes housing 4, piston rod 11, piston returnring 12 (i.e., part of a piston rod reset feature), dose knob 5, button6, and window 7 to view dose settings 8. At the proximal end of housing4 is a thread 9 and may include a radial stop 9 a or snap fit that worksto clearly define the radial position of the cartridge holder relativeto the dose setting mechanism after the reconstitution procedure whenthe device is in the ready-to-use state. The radial stop 9 a is designedto interact and abut a cooperating stop of snap fit feature on theterminal distal end of distal portion 50 b of the cartridge holder whenthe cartridge holder and dose setting mechanism have been screwedtogether and abut one another.

FIGS. 12A-12D illustrates a close-up of the return ring 12 removed andseparated from the dose setting mechanism 2 for clarity purposes. Theoutside surface 12 a of the return ring can contain a plurality oflongitudinal splines 12 b. These splines function as a gripping surfacefor the user to facilitate gripping and rotating the return ring in thecounter-clockwise direction (relative to the dose setting mechanism 2)when it becomes necessary to reset (retract) the piston rob back intothe dose setting mechanism to a starting position. These splines 12 balso function as an engagement surface for one or more guide elements170 (see FIGS. 13A-13C). The return ring 12 has an inner surface thatmay be non-circular and having a shape 310 that conforms to the pistonrod such that the return ring and the piston rod are axially fixed toeach other.

Guide elements 170 can be positioned on the inside surface 50 c ofcartridge holder 50 and configured with a plurality of longitudinalsplines 170 a that are designed to cooperate and engage with splines 12b. Guide elements 170 are rotationally fixed to the inside surface 50 cof the cartridge holder 50 and can be separate components that arefixedly attached to the inside surface or the guide elements can befabricated as integral parts of the inside surface, for example, througha molding process. When the cartridge holder and the dose settingmechanism are axially aligned with each other and then brought together,splines 170 a and 12 b will engage and axially slide relative to eachother forming a rotationally fixed engagement such that clockwiserotation of the cartridge holder (relative to the dose settingmechanism) will cause clockwise rotation of the return ring 12. Thisrotation of the return ring will cause rotation of the piston rod 11,which in turn will cause it to translate axially out of the dose settingmechanism in the proximal direction. The inner surface 12 c of thedistal end of return ring 12 is configured to engage the piston rod 11in a rotationally fixed manner, for example, by having a non-circularcross-section 310 as illustrated in FIGS. 12A-12D.

FIGS. 18A-18F present alternative design of the above describedinteraction between a cartridge holder 100 and a dose setting mechanism(not shown), where both assemblies are fully disposable. In this design,there is no return ring. Instead there is a piston rod guide 150 axiallyfixed within the dose setting mechanism and having two longitudinallyextending fingers 152 projecting proximally from a guide 153 havingnon-circular inner portion 154 that prevents relative rotation of thepiston rod. The fingers 152 are separated by a slit or gap 151 that isdesigned to slidably accept corresponding radial projections 101 fixedlyattached (both axially and rotationally) to the inside surface 102 ofcartridge holder 100. The dimension of the gaps 151 and/or projections101 are selected such that projections 101 fit within the gaps 151abutting the sides of the fingers 152 when the cartridge holder 100 isaligned with the dose setting mechanism. As the cartridge holder isscrewed into/onto the dose setting mechanism, the rotating projections101 engage the fingers 152 causing the piston rod guide 150 to engageand rotate. Rotation of the piston rod guide 150 also rotates the guide153 and non-circular portion 154, which engages and rotates the pistonrod. This causes the piston rod to translate axially forward in theproximal direction initiating the reconstitution process. Once thecartridge holder 100 has been fully assembled with the dose settingmechanism the piston rod guide 150 is locked rotationally relative tothe dose setting mechanism housing and therefore prevents rotation ofthe piston rod during dose setting and dose delivery.

The cartridge holder 50 accepts and securely holds cartridge 35,preferably through a snap fit connection between the bypass 21 and anotch or other secure connector located on or near the secondobservation window 22 (see FIGS. 13A-13C). The bypass 21 is part ofcartridge 35 and allows the solvent 37 (see FIGS. 16A-16E) to flow fromthe second or distal chamber 18 into the first or proximal chamber 19during the reconstitution process where the solvent solubilizes thelyophilized drug agent 38. The lyophilized drug is typically prepared asdescribed above.

The cartridge holder 50 has two observation windows 22, 23 (see FIGS.18A-18F). Window 23 can be a cut-out in the cartridge holder that allowsthe user to observe the solvent 37 that is initially contained inchamber 18 when the device is in the starting configuration. As thereconstitution process begins, window 23 will show the axial movement ofreturn ring 12 in the proximal direction as the cartridge holder isscrewed onto the dose setting mechanism via the engagement of threads 9and 300. Window 22 is also located in the cartridge holder 50 and canalso be a cut-out. Window 22 may also have notch that is designed toengage and secure bypass 21 of the cartridge 35 through, for example, asnap fit connection. This window 22 also enables the user to view thelyophilized drug agent before, during and after the reconstitutionprocess.

The exemplary multi-compartment cartridge 35 (see FIGS. 16A-16E) isshown as a dual chamber cartridge comprised of a first or proximalchamber 19 and a second or distal chamber 18. These chambers areseparated by a sliding piston or stopper, namely first stopper 26, theproximal end of chamber 19 is sealed by pierceable membrane or septum 37that is secured in place by a crimped metal cap 36. The proximal end ofcartridge 35 is sealed by a second sliding stopper 25. Solvent 37 iscontained between stoppers 25,26. Lyophilizate 38 containing the drugagent is in first chamber 19. FIGS. 16A-16E show the movement andchanging chamber configuration during the reconstitution process as thedelivery device transforms from the initial or starting configuration(see FIGS. 14A-14F) and progresses to the delivery ready configuration,the right-hand illustration in FIGS. 16A-16E. The flow of solvent aroundthe first stopper is also illustrated by arrows 41.

FIG. 11 shows the threaded tube-like cylinder having external threads 9located on an outer proximal surface of the dose setting mechanism 2.This threaded outside surface is configured to engage a cooperatingthread 300 located inside the distal portion of the cartridge holder(see FIGS. 13A-13C). In some designs, thread 300 can be a female thread,e.g., a helical groove, that will engage a nib located on the insidesurface of distal portion 17. A radial stop or snap feature 9 a can beincluded on thread 300 such that when the cartridge holder has beenfully screwed onto the dose setting mechanism the hard stop or snapfeature will engage a corresponding feature on the inside surface of thecartridge holder to provide a tactile feedback to the user that the twoparts are securely connected. In a design where the delivery device iscompletely disposable, this engagement is permanent such that a userwill not be able to reverse the rotation of the cartridge holderrelative to the dose setting sleeve. This permanent locking engagementcan be achieved by using an asymmetrically shaped protrusion, sometimesreferred to as an irreversible snap lock.

FIGS. 15A and 15B show the position of stoppers 25, 26 relative tobypass 21 after the reconstitution process is complete. As illustrated,chamber 18 is completely subsumed as stopper 25 has moved proximally andin abutment with stopper 26. At this stage the device 1 is now ready tobe primed and/or to perform an injection once a needle 200 is attachedto connection 24.

As with the embodiments described above, this embodiment is applicablewith a number of injection device designs. The pen-type injection deviceof FIGS. 11 to 16E is just one possible design of an injection device,one that is either completely reusable or a semi-disposable device,where after the reconstitution process is complete and after themedicament has been expelled from the cartridge through one moreinjections, the user detaches the cartridge holder containing the emptycartridge from the reusable dose setting mechanism and discards theassembly. A new assembly, containing a fresh cartridge, can then beconnected to the reusable dose setting mechanism and the reconstitutionprocess/medicament delivery sequence can be repeated. Alternatively, thedevice could be completely reusable, where the cartridge holder isdesigned for reuse as well and where the empty used cartridge is removedand replaced with a full cartridge.

Device 1 has a dose dial sleeve that translates in a longitudinaldirection during dose setting, dose correction mid dose delivery. A doseis set through rotation of dose knob 5, which causes the dose dialsleeve to move linearly in the distal direction. A dose is delivered bypushing button 6 on the end of the dose knob 5 in the opposite orproximal direction. This in turn causes the dose dial sleeve to movelinearly back (proximally) into the dose setting mechanism 2. Oneexemplary sequence of a possible dose setting mechanism is illustratedin 17A-17C, where the dose setting mechanism is shown in the zero-setdose position (“0” on scale 8), when the dose is set, that start of theinjection when button 6 is pressed, and the end of injection where thepiston rod has moved proximally an axial distance proportional to theset dose of medicament. The dose setting mechanism shown in FIGS. 7A-7Eis designed and configured to only allow setting of a fixedpredetermined dose that is signified by “GO” on scale 8.

The pen-type injector design shown in FIGS. 11 to 18F will now bedescribed with more detail as to the component parts and theiroperation. The complete injection device 1 is illustrated in thezero-dose state as indicated by scale 8 showing a zero through thewindow 7 of housing 4. FIGS. 15A and 15B show the device t with aprotective cap removed to expose the cartridge holder 50 having a penneedle 200 connected to a needle connector 24 at the proximal end (seeFIGS. 13A-13C). A double-ended pen needle is typically used mounted in ahub and attached to needle connector 24 through a snap fit, thread.Luer-Lok, or other secure attachment with that the double ended needlecannula can achieve fluid communication with reconstituted medicament 39within chamber 19 of cartridge 35 positioned within cartridge holder 50.The cartridge 35 is sealed at the proximal end by septum 37 (see FIGS.16A-16E).

As mentioned, the dose setting mechanism can be designed and configuredas a fixed dose device. Alternatively, the dose setting mechanism couldallow for setting of one or more user selected doses through therotation of the dose knob 5 relative to housing 4. Part of the dosesetting mechanism of most pen-type injectors is a piston rod 11 that insome cases has a non-circular cross-section with two flat surfaces thatare designed to prevent the piston rod from rotating, but allows it tomove linearly in the proximal direction. As the piston rod movesproximally it pushes stoppers 25,26 proximally to expel medicament 39.The piston rod 11 is held in a non-rotational state relative to housing4 during both dose setting and dose delivery because it is arrangedwithin a non-circular pass through hole in the center of a piston rodguide in the case of a fully disposable device or in the piston rodreturn ring when the device is design as a rescuable device. In eitherdesign, during dose setting and dose delivery the piston rod guide orreturn ring is both rotationally and axially fixed to housing 4. Thisfixation can be achieved when the piston rod guide is a separatecomponent from the housing 4. The return ring becomes rotational fixedrelative to the housing when the cartridge holder is fully attached tothe dose setting mechanism.

The priming features described above are applicable to the embodimentsshown in FIGS. 11 to 18F. The same is true of the dose cancelingprocedure.

During dose setting, the dose knob 5 translates out and away from thedistal end of housing 4. As the dose dial sleeve rotates and translatesdistally, the progress of the dose setting (or dose cancellation) isobserved in window 7 as printed indicia on the dose dial sleeve movespast the window. When a desired dose setting is reached the indicia forthat dose will appear in the window. At this point the injection device1 is ready for a priming procedure or, if already primed, the deliveryof the medicament to an injection site. In either the case, the userwill push button 6 on the dose knob in the proximal direction until thezero-dose hard stop is reached and a zero-dose indicia is observed inthe window. During a priming step the user will observe whethermedicament is expelled out of the cannula of a pen needle. If nomedicament is expelled this means the piston rod is not in abutment withthe distal face of sliding piston or stopper 25. The priming step isthen repeated until medicament is observed exiting the cannula.

The dose setting mechanism of the present disclosure can also have amaximum dose hard stop feature that prevents a user from setting a dosegreater than the highest predetermined dose setting.

Once a dose has been dialed on the dose setting mechanism, the user canthen exert an axial force in the proximal direction on button 6 toinitiate the dose delivery procedure. The axial force exerted by theuser overcomes a distally directed force exerted by a biasing membercausing the piston rod 11 to move axially in the proximal direction.Axial movement of the piston rod causes the sliding stoppers to alsomove axially relative to the inside walls of chamber 19 of thestationary cartridge 35 forcing an amount of medicament 39 out of theneedle cannula 6 that is equivalent to the dose that was set by the userduring the dose setting procedure.

If the device is configured as a disposable injection device, then thecartridge 35 is not replaceable because the connection between thecartridge holder 50 and the housing 4 is permanent. Only throughbreaking or deformation of this connection can the cartridge be removedfrom the injection device. Such a disposable device is designed to bethrown out once the medicament has been expelled from the cartridge.

It is to be understood that the embodiments described above and shown inthe drawings are to be regarded only as non-limiting examples of thepossible designs of the safety assembly and such designs may be modifiedin many ways within the scope of the patent claims.

What is claimed is:
 1. A medicament delivery device for delivery of amedicament mixed within a multi-chambered cartridge, comprising: adistal part comprising a dose setting mechanism having a housing and apiston rod configured to move axially along the longitudinal axis of thehousing during dose delivery; and a proximal part comprising a screwdriven sleeve and a cartridge holder configured to accept a multichambered cartridge, the screw driven sleeve configured for attachmentto the distal part and when the screw driven sleeve is rotated relativeto the cartridge holder a medicament mixing process is performed withinthe multi-chambered cartridge.
 2. The medicament delivery device ofclaim 1, wherein the screw driven sleeve has a start position such thatthe screw driven sleeve extends distally from the cartridge holder. 3.The medicament delivery device of claim 1, wherein the screw drivensleeve has an end position where the screw driven sleeve is retractedproximally into the cartridge holder.
 4. The medicament delivery deviceof claim 1, wherein the screw driven sleeve further comprises a snap armlocated on an outside surface.
 5. The medicament delivery device ofclaim 4, wherein an assembly of the cartridge holder, themulti-chambered cartridge and the screw driven sleeve is configured tobe disposable, and a, protrusion on the snap arm is configured to engagea snap window in a non-releasable and permanent attachment such that thescrew driven sleeve is not capable of being rotated relative to thecartridge holder.
 6. The medicament delivery device of claim 4, whereinthe cartridge holder further comprises snap windows configured tointeract and engage with the snap arm.
 7. The medicament delivery deviceof claim 4, wherein when the screw driven sleeve is in a start position,the snap arm is releasably engaged with a first snap window on thecartridge holder or when the medicament mixing process is complete thescrew driven sleeve is fully positioned inside the cartridge holder andthe snap arm is engaged with a second snap window on the cartridgeholder.
 8. The medicament delivery device of claim 1, wherein themedicament delivery device is completely disposable.
 9. The medicamentdelivery device of claim 1, the cartridge holder has a cut-out or snapwindow.
 10. The medicament delivery device of claim 9, wherein thecut-out or snap window is configured to interact with a flexible or snaparm located on an outside of the screw driven sleeve.
 11. The medicamentdelivery device of claim 10, wherein the snap arm on the screw drivensleeve has an outward radially extending protrusion configured to engagethe cut-out or snap window.
 12. The medicament delivery device of claim10, wherein when the screw driven sleeve is in a start position, thesnap arm is releasably engaged with the snap window.
 13. The medicamentdelivery device of claim 10, wherein, when a reconstitution process iscomplete, the screw driven sleeve is fully positioned inside thecartridge holder and the snap arm is engaged with the snap window. 14.The medicament delivery device of claim 13, wherein an engagement of aprotrusion with the snap window is non-releasable, such that the screwdriven sleeve is not capable of being rotated relative to the cartridgeholder.
 15. The medicament delivery device of claim 1, furthercomprising a radial stop or snap fit defining the radial position of thecartridge holder relative to the dose setting mechanism after areconstitution procedure when the medicament delivery device is in aready-to-use state.
 16. The medicament delivery device of claim 1,wherein the medicament delivery device is provided to an end user withthe cartridge snapped into a cartridge container and the screw drivensleeve snapped into the cartridge holder through engagement of a snaparm with a snap window.
 17. The medicament delivery device of claim 1,further comprising fasteners that cooperate to permanently connect thedistal and proximal parts of the medicament delivery device to eachother.
 18. The medicament delivery device of claim 17, wherein thefasteners cooperate to form an irreversible snap fit.
 19. The medicamentdelivery device of claim 1, wherein, once the cartridge holder is fullyattached to the dose setting mechanism the connection is fixed,permanent and irreversible, preventing a user from disassembling thecartridge holder from the dose setting mechanism without physicallybreaking or destroying the medicament delivery device.
 20. Themedicament delivery device of claim 1, wherein the cartridge is held inplace in the cartridge holder through a snap-in notch that accepts aradially protruding bypass section of the cartridge.
 21. The medicamentdelivery device of claim 1, wherein the piston rod is configured toexert an axial force in a proximal direction on a distal stopper causingthe distal stopper to move proximally relative to an inside wall of thecartridge.
 22. The medicament delivery device of claim 21, wherein thedistal stopper is a second stopper, and the force on the second stopperis directly transferred to a first stopper because the liquid solvent ina second chamber is incompressible such that both the first and secondstoppers, and the solvent located between them, each move axiallyforward towards a bypass section of the cartridge.
 23. The medicamentdelivery device of claim 22, wherein once the first stopper has movedinto alignment with the bypass, the solvent can then flow from thesecond chamber around the first stopper and empty into a first chamberwhere it contacts the lyophilized drug agent and reconstitution begins.24. The medicament delivery device of claim 23, wherein as the cartridgeholder is configured to rotate and move relative to the screw drivensleeve, the cartridge is configured to move relative to the stationarypiston rod, so as to push the second stopper axially in the proximaldirection inside the cartridge until all the solvent is forced out ofthe second chamber and into the first chamber.
 25. The medicamentdelivery device of claim 1, wherein the distal part comprises a dosesetting knob or an injection button.